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The Role of BDNF in a Triple Transgenic Mouse Model of Alzheimer¡¦s Disease

Jean Zhang Honeywell
B.S. Biology, The College of New Jersey - 2003

Thesis Advisor: Cheryl F. Dreyfus, Ph.D.
Graduate Program Neuroscience

3rd Floor Classrooms
RWJ-School of Public Health
683 Hoes Lane, Piscataway

Tuesday, November 22, 2011
9:30 a.m.


Alzheimer”¦s disease (AD) is associated with a loss of basal forebrain (BF) cholinergic neurons and their myelin ensheathment. The identification of molecules that impact these processes is critical. Previous work in culture and in vivo found that brain derived neurotrophic factor (BDNF), a member of the neurotrophin gene family, may be one such factor. BDNF increases DNA synthesis and differentiation of oligodendrocyte (OLG) lineage cells from the BF. BDNF also increases the survival and function of BF cholinergic neurons. I hypothesize, then, that one molecule that may affect these cells in AD is BDNF. Effects of BDNF were assessed on OLGs and cholinergic neurons of the BF in control and in the mouse triple transgenic model of Alzheimer”¦s disease (3xTg- AD).

To begin to explore the role of BDNF in aging AD mice, initial developmental studies compared the BF of the 3xTg-AD mice to the BF of similarly aged controls. Coincident decreases are revealed in the AD mice at 12 mos in choline acetyltransferase (ChAT)+ neurons, CC1+ post-mitotic OLGs, the differentiated OLG traits myelin basic protein (MBP) and myelin associated glycoprotein (MAG) as well as the OLG progenitor marker, NG2 protein. There is also a decrease in BDNF levels in the BF of 3xTg-AD mice at 12 mos but not before. The data suggest that BDNF impacts both the OLG and cholinergic neuron population in the BF of the 3xTg-AD mice during a critical time period.

To investigate the possibility that BDNF may reverse these deficits, exogenous BDNF (0.5ug/ul) or vehicle, artificial cerebrospinal fluid (aCSF) was stereotaxically injected into the lateral ventricle of control and 3xTg-AD mice. 12 mos old 3xTgAD mice injected with BDNF exhibit increased MBP, MAG and ChAT activity in the BF after a week compared to control mice injected with aCSF. In contrast, NG2 protein levels and the numbers of CC1+ cells and ChAT+ cells are not affected by exogenous BDNF, suggesting that BDNF reverses mature OLG traits and cholinergic neuronal function specifically.

To evaluate the possibility that BDNF also affects pathological factors associated with AD, beta-amyloid (A„µ) and phosphorylated tau levels in the BF were assessed. Elevated levels of A„µƒnare observed at 12 mos in the BF, but not previously, suggesting that they may be associated with the deficits in cholinergic neurons, oligodendrocytes and BDNF also noted at 12 mos. On the other hand, there is no phosphorylated tau observed at 12 mos in the BF. When exogenous BDNF was injected at 12 mos it resulted in decreases in A„µ. These data indicate that elevation of BDNF may reverse the functional deficits of oligodendrocyte and cholinergic neurons as well A„µƒnin the BF of the 3xTg-AD mice and serve as a therapeutic agent for Alzheimer”¦s disease. Supported by NIH HD 23315

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